Lintuzumab-Ac225 in Older Acute Myeloid Leukemia (AML) Patients

NCT02575963 | Completed Phase 1

• 1 other identifier: API-01
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 17

Brief Summary

The study is a multicenter, open label Phase I/II trial.

1. 1.Establish the MTD of fractionated doses of Lintuzumab-Ac225 in combination with low dose cytosine arabinoside (Low Dose Ara-C, LDAC) (Phase 1 portion)
2. 2.Determine the response rate (CR + CRp + CRi) to fractionated doses of Lintuzumab-Ac225 alone (Phase 2 portion)

Conditions

AML

Outcome Measures

Primary Outcomes (2)

• Phase I: Maximum Tolerated Dose (MTD) of Lintuzumab-Ac225

  If two or more patients in a cohort experience dose limiting toxicity (DLT), then maximum tolerated dose (MTD) will have been exceeded, and no further dose escalation will occur. If only three patients were treated at a dose level under consideration as the MTD, then up to three additional patients will be accrued. If no more than one of the six patients at that dose level experiences DLT, then that dose level will be confirmed as the MTD.

  Cycle 1, up to 52 days

• Phase II: CR+CRp+CRi

  The primary objective is to determine the antileukemic effects, including its ability to produce complete remissions, of Lintuzumab-Ac225.

  First evaluation at 42 days after treatment

Secondary Outcomes (4)

• Phase II: PFS

  1 year

• Phase II: LFS

  1 year

• Phase II: OS

  1 year

• Phase II: Toxicity Spectrum

  1 year

Study Arms (1)

Phase 1 (Completed)

EXPERIMENTAL

Cytarabine + Lintuzumab-Ac225 Cytarabine days 1 to 10 of each cycle. Doses were divided into 2 equal fractions with the first fraction given approx. 4-7 days after 1 cycle of low dose cytarabine and the second fraction given 4-7 days after the first fraction, followed by up to 11 more cycles. Furosemide (Phase 1 only) and Spironolactone were administered after Lintuzumab-Ac225. Experimental: Phase 2 Experimental: Lintuzumab-Ac225 The Phase II dose determined during the Phase I dose escalation was 4.0 μCi/Kg Lintuzumab-Ac225 and 25 μg/Kg unlabeled HuM195 divided into 2 equal fractions with the first fraction given on Day 1 and the second fraction given on Day 5-8. Spironolactone is administered after Lintuzumab-Ac225.

Drug: Cytarabine (Phase 1 only); Biological: Lintuzumab-Ac225; Drug: Furosemide (Phase 1 only); Drug: Spironolactone

Interventions

Cytarabine (Phase 1 only) DRUG

Low dose cytarabine administered at 20 mg subcutaneously every 12 hours for the first 10 days (Days 1 to 10) of every cycle. Cycle 1 can last up to 52 days (depending on the schedule of study drug dosing) in order to allow for recovery from Lintuzumab-Ac225. Cycles 2-12 will last 28 days each.

Also known as: Low dose Ara-C, LDAC

Phase 1 (Completed)

Lintuzumab-Ac225 BIOLOGICAL

In Phase 1 the starting dose level was 1.0 μCi/Kg of Lintuzumab-Ac225 and 15 μg/Kg unlabeled HuM195 divided into 2 equal fractionated doses (0.5 μCi/Kg and 7.5 μg /Kg + 0.5 μCi/Kg and 7.5 μg /Kg) with the first fraction administered approximately 4-7 days after 1 cycle of low dose cytarabine and the second fraction administered 4-7 days after the first fraction, followed by up to 11 more cycles. In Phase 2 the dose will be 4.0 μCi/Kg Lintuzumab-Ac225 and 25 μg/Kg unlabeled HuM195 divided into 2 equal fractions with the first fraction given on Day 1 and the second fraction given on Day 5-8.

Also known as: HuM195-Ac225, Actimab-A

Phase 1 (Completed)

Furosemide (Phase 1 only) DRUG

40 mg by mouth daily one day prior to treatment with Lintuzumab-Ac225 and continuing for 10 days following administration of the 2nd divided dose.

Also known as: Lasix

Phase 1 (Completed)

Spironolactone DRUG

25 mg by mouth daily, administered 10 days after second dose of 225Ac-HuM195 and continued for 12 months.

Also known as: Aldactone

Phase 1 (Completed)

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents or hypomethylating agents for this diagnosis. Patients with other prior cancer diagnoses are allowed as long as they have no measurable disease, are not undergoing active therapy, and have a life expectancy of ≥ 4 months.
• Patients age ≥60 years who:
• Are unwilling to receive intensive (e.g. 7+3) chemotherapy, or
• Have poor-risk prognostic factors defined as antecedent hematologic disorder, prior chemotherapy or XRT, abnormal karyotype other than t(8;21), inv16, or t(16;16), any karyotype with FLT3-ITD, or presenting WBC\>100K, or
• Have significant comorbidities, that in the judgment of the investigator makes the subject unsuitable for standard dose induction chemotherapy (e.g. anthracycline and infusional cytarabine given as 7+3), or;
• Any patient age ≥ 70 years.
• Blast count ≥20%
• Greater than 25% of blasts must be CD33 positive.
• Adequate renal and hepatic function
• ECOG ≤ 3
• Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents for this diagnosis.
• Patients age ≥60 years who:
• Patients ≥60 years unfit to receive intensive (e.g., 7+3) chemotherapy who have:
• Congestive heart failure or documented cardiomyopathy with an EF ≤50%, provided that EF ≥35% or,
• Documented pulmonary disease with DLCO ≤65% or FEV1 ≤65%, provided that patients do not require more than 2 L of oxygen per minute or,

You may not qualify if:

• Patients with acute promyelocytic leukemia
• Treatment with chemotherapy or biologic therapy within 3 weeks, except for hydroxyurea, which must be discontinued prior to treatment on study
• Treatment with radiation within 6 weeks
• Active serious infections uncontrolled by antibiotics
• Active malignancy within 2 years of entry, except previously treated non-melanoma skin cancer, carcinoma in situ or cervical intraepithelial neoplasia, and organ confined prostate cancer with no evidence of progressive disease based on PSA levels and are not on active therapy.
• Clinically significant cardiac or pulmonary disease
• Patients with liver cirrhosis
• Active CNS leukemia. Patients with symptoms of CNS involvement, particularly those with M4 or M5 subtypes, should undergo lumbar puncture prior to treatment on study to exclude CNS disease. Symptoms include cranial neuropathies, other neurologic deficits, and headache.
• Psychiatric disorder that would preclude study participation

Sponsors & Collaborators

• Actinium Pharmaceuticals: lead

Study Sites (17)

UCLA Medical Center, Division of Hematology/Oncology

Los Angeles, California, 90095, United States

Location

University of Kentucky, Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

University of Louisville, James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

Ochsner Medical Center, The Gayle and Tom Benson Cancer Center

New Orleans, Louisiana, 70121, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Weill Medical College of Cornell University

New York, New York, 10021, United States

Location

Columbia University Medical, Herbert Irving Comprehensive Cancer Center

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Duke Cancer Center

Durham, North Carolina, 27705, United States

Location

University of Pennsylvania, Perelman Center for Advanced Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

St. Francis Cancer Center

Greenville, South Carolina, 29607, United States

Location

Baylor Scott and White Research Institute, Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Swedish Cancer Institute, Center for Blood Disorders and Stem Cell Transplantation

Seattle, Washington, 98104, United States

Location

Fred Hutchinson Cancer Research Center

Seattle, Washington, 98109, United States

Location

West Virginia University, Mary Babb Randolph Cancer Center

Morgantown, West Virginia, 26506, United States

Location

Medical College of Wisconsin Cancer Center

Milwaukee, Wisconsin, 53226, United States

Location

VA Caribbean Healthcare System

San Juan, 00921, Puerto Rico

Location

Related Publications (4)

• Larson SM, Carrasquillo JA, Cheung NK, Press OW. Radioimmunotherapy of human tumours. Nat Rev Cancer. 2015 Jun;15(6):347-60. doi: 10.1038/nrc3925.

  PMID: 25998714 BACKGROUND

• Jurcic JG, Rosenblat TL. Targeted alpha-particle immunotherapy for acute myeloid leukemia. Am Soc Clin Oncol Educ Book. 2014:e126-31. doi: 10.14694/EdBook_AM.2014.34.e126.

  PMID: 24857092 BACKGROUND

• Scheinberg DA, McDevitt MR. Actinium-225 in targeted alpha-particle therapeutic applications. Curr Radiopharm. 2011 Oct;4(4):306-20. doi: 10.2174/1874471011104040306.

  PMID: 22202153 BACKGROUND

• Nikitaki Z, Velalopoulou A, Zanni V, Tremi I, Havaki S, Kokkoris M, Gorgoulis VG, Koumenis C, Georgakilas AG. Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair. Expert Rev Mol Med. 2022 Mar 31;24:e15. doi: 10.1017/erm.2022.6.

  PMID: 35357290 DERIVED

Related Links

• Phase I trial of alpha-particle immunotherapy with 225Ac-lintuzumab and low-dose cytarabine in patients age 60 or older with untreated acute myeloid leukemia.
• Phase I Trial of Targeted Alpha-Particle Immunotherapy with Actinium-225 (225Ac)-Lintuzumab (Anti-CD33) and Low-Dose Cytarabine (LDAC) in Older Patients with Untreated Acute Myeloid Leukemia (AML)

MeSH Terms

Interventions

Cytarabine; Furosemide; Spironolactone

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Lactones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Avinash Desai, MD

  Actinium Pharmaceuticals Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 7, 2015
• First Posted: October 15, 2015
• Study Start: October 1, 2012
• Primary Completion: November 1, 2018
• Study Completion: May 1, 2020
• Last Updated: July 20, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

PR (1); US (16)